Abstract

Background:In clinical trials, the use of inhaled corticosteroids is associated with an increased risk of pneumonia in people with COPD, but whether the same is true for people with asthma is not known.

Methods:With the use of primary care data from The Health Improvement Network, we identified people with asthma, and from this cohort, we identified patients with pneumonia or lower respiratory tract infection and age- and sex-matched control subjects. Conditional logistic regression was used to determine the association between the dose and type of inhaled corticosteroid and the risk of pneumonia or lower respiratory tract infection.

Results:A dose-response relationship was found between the strength of inhaled corticosteroid dose and risk of pneumonia or lower respiratory tract infection (P < .001 for trend) such that after adjusting for confounders, people receiving the highest strength of inhaled corticosteroid (≥ 1,000 μg) had a 2.04 (95% CI, 1.59-2.64) increased risk of pneumonia or lower respiratory tract infection compared with those with asthma who did not have a prescription for inhaled corticosteroids within the previous 90 days.

Conclusions:People with asthma receiving inhaled corticosteroids are at an increased risk of pneumonia or lower respiratory infection, with those receiving higher doses being at greater risk. Pneumonia should be considered as a possible side effect of inhaled corticosteroids, and the lowest possible dose of inhaled corticosteroids should be used in the management of asthma.

Inhaled corticosteroids (ICSs) are prescribed widely to people with asthma1 and COPD2 to improve symptoms, maximize lung function, and reduce exacerbation risk. Evidence suggests that ICS use may be associated with an increased risk of pneumonia in people with COPD.3‐5

Although asthma is an independent risk factor for invasive pneumococcal disease,6 it is not known whether ICSs are independently associated with an increased risk of pneumonia in people with asthma. We set out to examine whether ICSs are associated with an increased risk of pneumonia or lower respiratory tract infection (LRTI) in people with asthma by using computerized primary care data and a matched case-control design.

Materials and Methods

We extracted data from The Health Improvement Network database (www.thin-uk.com). This database contains electronic medical records of 9.1 million patients collected from > 479 general practices in the United Kingdom. We identified a cohort of people with a recorded diagnosis of asthma after January 4, 2004, aged 18 to 80 years. We performed a nested case-control study in this cohort, with cases defined by the first-recorded diagnosis of pneumonia or LRTI by previously defined Read codes for pneumonia.7 The date of the diagnosis of pneumonia or LRTI was considered the index date. From the remaining population of people with asthma, six control subjects per patient were matched on the basis of sex and age at index date (within 3 years). Patients and control subjects with COPD were excluded from the dataset. Ethics approval to use data from The Health Improvement Network was given by the NHS South-East Multi-center Research Ethics Committee for studies that use precollected, anonymized data (reference number 07/H1102/103).

The main hypothesis was that the risk of pneumonia or LRTI would be associated with the current use of ICS, and for this reason, we initially identified all prescriptions for ICS up to 90 days before the index date. In the United Kingdom, the average duration of a prescription is up to 90 days. We grouped ICSs according to type as follows: beclomethasone dipropionate; fluticasone propionate, budesonide; and a combined group of ciclesonide and mometasone furoate that was not presented in all analyses because of small numbers. Where the type of ICS was changed in the previous 90 days, we defined exposure according to the last prescription. We excluded individuals who were prescribed more than one type of ICS inhaler on the same day (n = 78).

To define the dose of ICS, we used the dose of drug delivered with each inhalation because information on puffs prescribed per day is recorded inconsistently in primary care datasets. To allow for different dose equivalence between drugs, budesonide was considered equivalent to beclomethasone, and a dose multiplying factor of 2 for fluticasone propionate was used. For each drug type, we defined a high and a low dose based on a cut point of 200 μg, except for fluticasone where we used a cut point of 250 μg. These cut points represent the step at which a long-acting β2-agonist is introduced according to UK asthma guidelines.1

The a priori confounders were smoking status (most recent recording) and comorbidity as defined by the Charlson Comorbidity Index score.8 Other potential confounders considered were influenza vaccination in the previous year, number of courses of reliever inhalers in the previous year (both total and separated by short-acting β2-agonists and long-acting β2-agonists), effect of oral corticosteroids (number of courses in the year before the index date), and Townsend socioeconomic status score.

We estimated the association between ICS use and pneumonia or LRTI by conditional logistic regression and various different exposures, including, in a stepwise fashion, type of ICS, dose of ICS, and a combination of type and dose of ICS. We then adjusted the models for a priori confounders and included other confounders if they altered the ORs for the exposure and outcome association by > 10%.

We performed a number of sensitivity analyses to determine whether the effect was similar in different patient populations and examined whether the effect was similar for the diagnosis of pneumonia vs LRTI. We examined the data after excluding patients with bronchiectasis. We also examined the data only in those who had not changed the type of inhaler in the previous 90 days and included the number of short-acting and long-acting inhalers in the past year separately in the model. All analyses were completed with Stata 11 software (StataCorp LP).

Results

We identified 6,857 patients with asthma and pneumonia or LRTI and 36,312 age- and sex-matched control subjects from a cohort of 359,172 people with asthma (Table 1). The mean age of the population was 54 years (range, 18-80 years). Patients with asthma and pneumonia or LRTI were more likely to smoke, had a higher Charlson Comorbidity Index score (ie, more comorbid illness), and were from a lower social class compared with control subjects (Table 1). Patients were more likely to have received a flu vaccination in the previous year (Table 1) and to use more reliever inhalers and had more prescriptions for oral steroids in the previous year than control subjects (Table 2).

Patients with asthma and pneumonia or LRTI were more likely to have a prescription for ICS in the past 90 days than control subjects (Table 2). After adjusting for confounders, the OR for this association was 1.24 (95% CI, 1.15-1.33) (Table 3).

Individuals taking ciclesonide/mometasone were excluded from the analyses because of small numbers. LRTI = lower respiratory tract infection. See Table 2 legend for expansion of other abbreviation.

a

Adjusted for number of relievers in the past year, Charlson Comorbidity Index score, smoking, social class, and use of oral steroids in the past year.

b

Restricted to individuals aged < 40 y who did not have bronchiectasis and did not change steroid in the previous 90 d and adjusted for number of relievers in the past year, Charlson Comorbidity Index score, smoking, social class, and use of oral steroids in the past year.

c

Was not able to determine strength in 25 individuals.

Steroid Type

We examined the risk of pneumonia or LRTI by ICS type. After adjusting for confounders, budesonide use demonstrated a small increased risk for pneumonia or LRTI (OR, 1.20; 95% CI, 1.06-1.35; P = .003). There was a higher risk of pneumonia or LRTI in patients receiving fluticasone propionate (OR, 1.64; 95% CI, 1.50-1.79; P < .001). None of the remaining steroid inhalers was associated with evidence of an increased risk (Table 3).

For fluticasone propionate the results were consistent if the 267 individuals who changed their steroid inhaler in the previous 90 days were excluded. The results were also similar when the cases were separated by diagnosis of LRTI or pneumonia; the OR for fluticasone propionate use and risk of LRTI (n = 3,410) was 1.67 (95% CI, 1.46-1.91) and for the risk of pneumonia (n = 3,447), 1.56 (95% CI, 1.38-1.77). The results were consistent when patients with bronchiectasis were excluded and when the number of short- and long-acting reliever inhalers were included separately in the model.

Steroid Dose

Of the patients with asthma and pneumonia or LRTI, 1.7% were prescribed the highest doses of ICSs (≥ 1,000 μg) compared with only 0.6% of the control subjects (P < .001). There was a dose-response relationship between strength of ICS and infection risk (P < .001 for trend) such that after adjusting for confounders, patients receiving the highest doses of ICSs were 2.04 (95% CI, 1.59-2.64) times more likely to have pneumonia or LRTI (Table 3).

These results remained consistent in the various sensitivity analyses and after excluding the 267 patients with a change of inhaler in the previous 90 days (OR for steroid dose ≥ 1,000 μg, 1.99; 95% CI, 1.54-2.57; P < .001 for trend). When separating the patient cases into pneumonia or LRTI, the effect was stronger for pneumonia; for the highest doses of ICSs (≥ 1,000 μg), the OR for pneumonia (n = 4,393) was 2.37 (95% CI, 1.67-3.37; P < .001 for trend) compared with the OR for LRTI (n = 4,666) (1.75; 95% CI, 1.21-2.53; P < .001 for trend).

Steroid Dose and Type Combined

There was a significantly increased risk of pneumonia or LRTI in patients with asthma receiving beclomethasone, budesonide, and fluticasone, but only fluticasone when the analysis was restricted to those aged < 40 years without bronchiectasis (Table 4). To control for asthma severity as a confounder, we restricted the analyses to patients only receiving ICS, with those receiving low-dose beclomethasone as the baseline group. With this restricted dataset in the adjusted analyses, we found that patients prescribed high-dose beclomethasone were 24% more likely to have an episode of pneumonia or LRTI (OR, 1.24; 95% CI, 0.99-1.54). Prescriptions of low- and high-dose budesonide and low- and high-dose fluticasone increased the risk of infection; the largest effect was found in patients prescribed high-dose fluticasone, who had an 87% (OR, 1.87; 95% CI, 1.63-2.15) increased risk of having pneumonia or LRTI compared with those prescribed low-dose beclomethasone (Table 5).

Individuals taking ciclesonide/mometasone were excluded from the analyses because of small numbers. See Table 2 and 3 legends for expansion of abbreviations.

a

Adjusted for number of relievers in the past year, Charlson Comorbidity Index score, smoking, social class, and use of oral steroids in the past year.

b

Restricted to individuals aged < 40 y who did not have bronchiectasis and did not change steroid in the previous 90 d and adjusted for number of relievers in the past year, Charlson Comorbidity Index score, smoking, social class, and use of oral steroids in the past year.

Table 5—Restricted Analysis of Association Between Type and Dose of ICS in Patients With a Prescription for Steroids in the Past 90 d and Risk of Pneumonia or LRTI, With Low-Dose Beclomethasone as Control (n = 9,324)

Individuals taking ciclesonide/mometasone were excluded from the analyses because of small numbers. See Table 2 and 3 legends for expansion of abbreviations.

a

Adjusted for number of relievers in the last year, Charlson Comorbidity Index score, smoking, social class, and use of oral steroids in the past year.

b

Restricted to individuals aged < 40 y who did not have bronchiectasis and did not change steroid in the previous 90 d and adjusted for number of relievers in the past year, Charlson Comorbidity Index score, smoking, social class, and use of oral steroids in the past year.

Discussion

To our knowledge, this study is the first to demonstrate a relationship between ICS use by type and dose and an increased risk of pneumonia or LRTI in asthma. Patients with asthma and pneumonia or LRTI were more likely to be receiving high-dose ICS. These results are consistent for a diagnosis of both LRTI and pneumonia and are similar after a number of different sensitivity analyses, including controlling for asthma severity. People with coexistent asthma and COPD were excluded from the analysis, and the results remained consistent when restricted to people aged < 40 years, negating any residual confounding effect of COPD. There was a clear dose-response relationship, with higher prescribed doses of ICS being associated with a higher risk of infection. The only ICS associated with an increased risk of LRTI or pneumonia across all analyses was fluticasone propionate.

A major strength of this study is the population size. To our knowledge, it is the largest to date, with 6,857 cases of pneumonia or LRTI identified. The associations described remained consistent after a number of sensitivity analyses, including an examination of effect in different age populations.

The use of data from primary care records has limitations. We cannot confirm compliance with ICS use or assess device type. Furthermore, individuals may be using a drug that was prescribed before the 90-day index period; however, this misclassification would bias the results toward the null hypothesis. The present study also shares a similar limitation to studies of pneumonia in COPD, namely that pneumonia was not confirmed radiographically; however, the diagnosis of pneumonia and LRTI has been previously shown to be reasonably accurate.7

Lower lung function9 is known to be associated with an increased risk of pneumonia, with more severe asthma and lower lung function carrying the highest risk; however, the increased risk of pneumonia or LRTI remained despite correction for age, smoking status, and Charlson Comorbidity Index score, reducing the effect of these limitations. We also corrected for the number of oral steroids prescribed in the past year, which is associated with both disease severity and decline in lung function,10 and for use of reliever inhalers, which is associated with an increased risk of an adverse asthma outcome.11

Because asthma severity is an independent risk factor for pneumonia,6,12 we attempted to control for asthma severity as a confounder by restricting the analysis. We used low-dose beclomethasone as the baseline and analyzed only those patients who received ICSs. The analysis did not substantially change the results, and the dose-response trend remained unaffected; however, we acknowledge that it is impossible to fully remove severity as a confounder.

The possibility that ICS may be associated with an increased risk of pneumonia in obstructive lung disease agreed with the results of the TORCH (Toward a Revolution in COPD Health) study,5 which examined the potential benefit of fluticasone propionate and salmeterol on mortality in COPD. The TORCH study reported a 19% 3-year rate of pneumonia in patients receiving fluticasone at ≥ 1,000 μg/d, corresponding to a significant 1.6-fold increase over placebo.

There have been few studies in asthma. O’Byrne and colleagues9 assessed the risk of pneumonia in a retrospective analysis of budesonide use in asthma. The primary dataset was all double-blind, placebo-controlled trials lasting at least 3 months that studied budesonide (26 trials, n = 9,067 for budesonide and n = 5,926 for the comparator); 62 cases of pneumonia were reported as either an adverse or a serious adverse event for budesonide compared with 82 for the comparator. In the primary dataset, the rate of pneumonia adverse events was 0.5% (10 of 1,000 patient-years) for budesonide and 1.2% (19.3 of 1,000 patient-years) for placebo. The occurrence of pneumonia serious adverse events was 0.15% for budesonide and 0.13% for placebo, resulting in a hazard ratio of 1.29 (95% CI, 0.53-3.12), which is similar to the present OR of 1.10 for budesonide and risk of pneumonia or LRTI. Overall, there was no increased risk with higher budesonide doses or any difference between budesonide and fluticasone propionate; however, pneumonia was not the primary end point in the trials.

Although the present data show a possible dose-response relationship, with higher doses of ICS being associated with an increased risk of pneumonia or LRTI, the biologic mechanism explaining the association between risk of infection in asthma and ICS is not clear. There is contradictory evidence on the ability of ICS to influence bacterial numbers. Mouse models13,14 and in vitro studies of human bronchial epithelial cells15,16 have demonstrated that ICSs reduce bacterial load or invasion, whereas steroid treatment can reactivate chronic infection by atypical bacteria in vitro and in animal models.17,18 People receiving ICS for chronic respiratory disease have also been found to have an increased risk of nontuberculous mycobacterial infection19,20 and altered airway microbiota compared with normal subjects.21 Studying the lung microbiota to delineate whether asthma itself or treatment with ICS alters the lung microbiome may help to answer questions of causation.

Conclusions

We show that ICSs are associated with an increased risk of pneumonia and LRTI in people with asthma. The results suggest that the dose of ICS prescribed should be kept to the minimum necessary to treat symptoms and that the dose should be stepped down if the patient is well controlled. Furthermore, prescribers should consider the possibility that infection rather than underlying asthma may be driving symptoms before increasing the ICS dose. This may be important before prescribers increase the ICS dose to treat recurring symptoms. A review and meta-analysis of asthma studies involving ICS and an exploration of the effect of ICS on the lung microbiota are now required.

Acknowledgments

Author contributions: Drs McKeever and Shaw had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Dr McKeever: contributed to the study design, analysis, and review of the manuscript.

Dr Harrison: contributed to the study design and review of the manuscript.

Dr Hubbard: contributed to the study design, analysis, and review of the manuscript.

Dr Shaw: contributed to the study design and writing of the first draft of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Harrison has received financial support from Boehringer Ingelheim GmbH and GlaxoSmithKline to attend scientific meetings and honorarium payments for advisory boards from GlaxoSmithKline, Napp Pharmaceuticals Limited, and Boehringer Ingelheim GmbH. Dr Hubbard has two Medical Research Council grants to investigate the causes and natural history of lung fibrosis and a Roy Castle clinical fellowship award to study care pathways for people with lung cancer. Dr Hubbard is the current GlaxoSmithKline/British Lung Foundation Professor of Respiratory Epidemiology. GlaxoSmithKline has cofunded a cohort study of lung biomarkers for people with idiopathic pulmonary fibrosis for which Dr Hubbard is a coapplicant. Drs McKeever and Shaw have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: The authors thank Christopher Smith, PhD, for help in the preparation of this manuscript.

Individuals taking ciclesonide/mometasone were excluded from the analyses because of small numbers. LRTI = lower respiratory tract infection. See Table 2 legend for expansion of other abbreviation.

a

Adjusted for number of relievers in the past year, Charlson Comorbidity Index score, smoking, social class, and use of oral steroids in the past year.

b

Restricted to individuals aged < 40 y who did not have bronchiectasis and did not change steroid in the previous 90 d and adjusted for number of relievers in the past year, Charlson Comorbidity Index score, smoking, social class, and use of oral steroids in the past year.

Individuals taking ciclesonide/mometasone were excluded from the analyses because of small numbers. See Table 2 and 3 legends for expansion of abbreviations.

a

Adjusted for number of relievers in the past year, Charlson Comorbidity Index score, smoking, social class, and use of oral steroids in the past year.

b

Restricted to individuals aged < 40 y who did not have bronchiectasis and did not change steroid in the previous 90 d and adjusted for number of relievers in the past year, Charlson Comorbidity Index score, smoking, social class, and use of oral steroids in the past year.

Table 5—Restricted Analysis of Association Between Type and Dose of ICS in Patients With a Prescription for Steroids in the Past 90 d and Risk of Pneumonia or LRTI, With Low-Dose Beclomethasone as Control (n = 9,324)

Individuals taking ciclesonide/mometasone were excluded from the analyses because of small numbers. See Table 2 and 3 legends for expansion of abbreviations.

a

Adjusted for number of relievers in the last year, Charlson Comorbidity Index score, smoking, social class, and use of oral steroids in the past year.

b

Restricted to individuals aged < 40 y who did not have bronchiectasis and did not change steroid in the previous 90 d and adjusted for number of relievers in the past year, Charlson Comorbidity Index score, smoking, social class, and use of oral steroids in the past year.

Return to: Inhaled Corticosteroids and the Risk of Pneumonia in People With Asthma

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